Meeting the Challenges of Insomnia in Your Patient Population

Co-Management Strategies, Standards of Care, and Emerging Pharmacotherapeutic Options

Karl Doghramji, MDProfessor of Psychiatry, Neurology, and MedicineMedical Director, Jefferson Sleep Disorders Center Thomas Jefferson UniversityPhiladelphia, Pennsylvania

Educational grant support was provided from Eisai.

Faculty Disclosure

• Dr. Doghramji: Consultant—Eisai, Purdue, Merck, Pfizer; Stock—Merck.

Disclosure

• The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration).– Dr. Doghramji will be discussing off-label use of medications in this presentation

and will identify those medications.

• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity.

• This activity has been independently reviewed for balance.

Learning Objectives

• Describe the relationship between insomnia and other psychiatric disorders in terms of bidirectional causality and the challenges of co-treatment

• Discuss current clinical guidelines for the management of chronic insomnia, recommended standards of care, and limitations of available therapies

• Evaluate clinical evidence surrounding emerging insomnia pharmacotherapies, including safety, efficacy, adverse events, and risk-to-benefit ratios

Prevalence of InsomniaSecond Highest Health-Related Complaint Worldwide

National Sleep Foundation. 2005 Adult Sleep Habits and Styles. www.sleepfoundation.org/professionals/sleep-america-polls/2005-adult-sleep-habits-and-styles. Accessed February 28, 2019. Buscemi N, et al. Manifestations and Management of Chronic Insomnia in Adults: Summary. Evidence Report/Technology Assessment No. 125. (Prepared by the Alberta Evidence-based Practice Center under Contract No. C400000021.) AHRQ Publication No. 05-E021-1. Rockville, MD: Agency for Healthcare Research and Quality. 2005. Sleep Report. www.sleepreviewmag.com. Accessed October 28, 2015.

Never 2%

Rarely 4.4%

A Few Nights per Month 25%

33% Every Night

21% A Few Nights per Week

Case

• 71-year-old c/o unrefreshing sleep following retirement • Onset 4 months ago• Frequency 4 to 5 nights/week• Mind “spins” at bedtime• Feels washed out during day; low energy, moody, irritable• No medical contributors• MSE: Psychomotor slowing; mood “fine”. Affect restricted, no h/s

ideation, sensorium clear. Cognitive functions intact

71-year-old c/o unrefreshing sleep 4 to 5 nights/week after retirement, 4 months ago; washed out, low energy, moody, irritable, meets MDD criteria.

What additional criterion must be met to satisfy criteria for DSM-5 insomnia disorder?

A. Duration of insomnia must be > 6 monthsB. Difficulty with insomnia must occur nightlyC. Sleep laboratory confirmation of a sleep latency (time to fall

asleep) > 1 hourD. Must not meet criteria for MDDE. Meets diagnostic criteria for insomnia disorder

MDD = major depressive disorder.

Insomnia DisorderA. Dissatisfaction with sleep quantity or quality with ≥ 1 of the following:

1. Difficulty initiating sleep (children: w/o caregiver intervention)2. Difficulty maintaining sleep (children: w/o caregiver intervention)3. Early morning awakening w/ inability to return to sleep

B. Significant distress or impairmentC. > 3 nights/weekD. > 3 monthsE. Adequate opportunity for sleepSpecify if:

– With non-sleep disorder mental comorbidity– With other medical comorbidity– With other sleep disorder

Criteria F, G, and H not shown; not all specifiers shown.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.

Insomnia and Hyperarousal

EEG = electroencephalogram; HPA = hypothalamic pituitary adrenal.

Cognitive arousal

Heightened brain

metabolism

Sympathetic activation

HPA axis activation

Increasedbody metabolic

rate

EEG arousal

Hyperarousal

Impairments Associated with Insomnia

• Diminished ability to enjoy family and social relationships

• Decreased quality of life• Increased absenteeism and

poor job performance• Motor vehicle crashes• Increased risk of falls• Increased health care costs

• Impaired concentration and memory

• Increased incidence of pain• Enhanced risk of present and

future psychiatric disorders• Hypertension• Diabetes• Increased mortality

Psychiatric Disorders Comorbid with InsomniaPoint Prevalence

N=580.Ford DE, et al. JAMA. 1989;262(11):1479-1484.

Dysthymia

Drug Abuse

No Psychiatric Disorder

Other Psychiatric Disorders

Alcohol Abuse

Patients (%)

10 600 40 5020 30

Major Depression

Anxiety Disorder

8.6

4.2

59.5

5.1

7.0

14.0

23.9

Complex Relationship between Insomnia and Mood Disorders

• Insomnia – Is a common complaint in MDD– Is more likely to emerge prior to, than during or after, MDD first

episode or recurrence– Is associated with higher rates of lifetime and current MDD and

suicide– Its presence and persistence predict future MDD– Predicts poorer outcome in MDD (persistence, chronicity,

suicidality)– Predicts the onset of mania in bipolar depression

McCall WV, et al. Curr Psychiatry Rep. 2013;15(9):389. Judd LL, et al. Arch Gen Psychiatry. 2008;65(4):386-394. Cho HJ, et al. Am J Psychiatry. 2008;165(12):1543-1550. Breslau N, et al. Biol Psychiatry. 1996;39(6):411-418. Ohayon MM, et al. J Psychiatr Res. 2003;37(1):9-15. Perlis ML, et al. Biol Psychiatry. 1997;42(10):904-913.

Sleep Disturbances as Residual Symptoms following Acute MDD Remission

Patients with major depressive disorder (N=215) received fluoxetine 20 mg for 8 weeks. Presence of residual symptoms not predicted by baseline demographic characteristics or Axis I and Axis II coexisting conditions. Nierenberg AA, et al. J Clin Psychiatry. 1999;60(4):221-225.

Mood

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Weight Psycho-motor

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Interest

Subthreshold

Threshold

Selected Comorbid Conditions and Treatment Examples

• Obstructive sleep apnea– CPAP, BIPAP, oral appliances, upper airway surgery

• Restless legs syndrome– Alpha 2-delta ligands, dopaminergic agents

• MDD– Antidepressants

• GERD– Proton pump inhibitors, H2 receptor blocker

• Shift work disorder– Bedtime melatonin, modafinil/armodafinil prior to shift, bright light therapy

• Medication-induced insomnia – Dosage or medication change

BIPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; GERD = gastroesophageal reflux disease.Doghramji K, et al. Focus: The Journal of Lifelong Learning in Psychiatry. 2009;7(4):441-445.

Insomnia Evaluation and Management Algorithm

Doghramji Karl, et al. Clinical Management of Insomnia. Second Edition. 2015. Department of Psychiatry and Human Behavior Faculty Papers. Paper 25.

Obtain details aboutcourse of insomnia

Possible short sleeper;supportive reassurance

Insomnia Disorder

Is insomnia contributingto decreased daytimefunctioning and quality

of life or worseningof chief complaint?

Does insomniaoccur

in isolation?

Is insomniaassociated with

comorbid medicalor psychiatric

condition?

Is use of insomniamedication unsafe

in this patient?

Treat withbehavioral therapy

Treat with behavioraland/or pharmacologic

therapy

No furthertreatment needed

Treatcomorbid

condition first

Is insomniapersistent?

YES

YES

YES

NO

YES

YES

NO

NO

NO

Treatments for Insomnia

• Cognitive-behavioral therapy• Alternative nutraceuticals • Nonprescription pharmacologic agents (over-the-counter)• Prescription pharmacologic agents

Psychological and Behavioral Treatments for Primary Insomnia

*Standard Treatment according to American Academy of Sleep Medicine.CBT = cognitive-behavioral therapy; OOB = out of bed. Morgenthaler T, et al.; American Academy of Sleep Medicine. Sleep. 2006;29(11):1415-1419. Bootzin RR, et al. J Clin Psychiatry. 1992;53 Suppl:37-41.

Techniques Method

Stimulus control therapy* If unable to fall asleep within 20 minutes, get OOB and repeat as necessary

Relaxation therapies* Biofeedback, progressive muscle relaxation

Restriction of time in bed (sleep restriction) Decrease time in bed to equal time actually asleep and increase as sleep efficiency improves

Cognitive therapy Talk therapy to dispel unrealistic and exaggerated notions about sleep

Paradoxic intention Try to stay awake

Sleep hygiene education Promote habits that help sleep; eliminate habits that interfere with sleep

CBT* Combines sleep restriction, stimulus control, and sleep hygiene education with cognitive therapy

Meta-analytic Support for Efficacy of CBT-i• 20 RCTs (1162 participants [64% female; mean age, 56 years]) • Approaches to CBT-i incorporated at least 3 of the following:

cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation

• At the posttreatment time point– SOL improved by 19.03 (95% CI, 14.12 to 23.93) minutes, – WASO improved by 26.00 (CI, 15.48 to 36.52) minutes,– TST improved by 7.61 (CI, 0.51 to 15.74) minutes, and – SE% improved by 9.91% (CI, 8.09% to 11.73%)

• Changes seemed to be sustained at later time points. No adverse outcomes were reported

CBT-i = cognitive-behavioral therapy for insomnia; RCT = randomized controlled trial; SE% = sleep efficiency; SOL = sleep onset latency; TST = total sleep time; WASO = wake after sleep onset.Trauer JM, et al. Ann Intern Med. 2015;163(3):191-204.

The Dos of Sleep Hygiene

• Get OOB at the same time every morning• Increase exposure to bright light during the day• Establish a daily activity routine• Exercise regularly in the morning and/or afternoon• Set aside a worry time• Establish a comfortable sleep environment• Do something relaxing prior to bedtime• Try a warm bath

Hauri PJ. In: Hauri PJ, ed. Case Studies in Insomnia; New York, NY: Plenum; 1991:65

The Don’ts of Sleep Hygiene

Avoid…• Alcohol• Caffeine, nicotine, and other stimulants• Exposure to bright light during the night• Exercise within 3 hours of bedtime• Heavy meals or drinking within 3 hours of bedtime• Using your bed for things other than sleep (or sex)• Napping, unless a shift worker • Watching the clock• Trying to sleep• Noise• Excessive heat/cold in room

Hauri PJ. In: Hauri PJ, ed. Case Studies in Insomnia; New York, NY: Plenum; 1991:65.

Effect of Blue Light Blocking on Sleep

Factors favoring the initial utilization of CBT over pharmacology in insomnia management include:

A. Need for more rapid clinical improvement

B. No comorbid medical conditions

C. History of, or present, substance use disorder

D. Time limitation

Pharmacotherapy vs CBT for Insomnia

Doghramji K, et al. Integrating psychotherapy and pharmacology in insomnia. In: de Oliveira, et al (Eds). Integrating Psychotherapy and Psychopharmacology (Clinical Topics in Psychology and Psychiatry). First Edition. New York, NY: Routledge; 2014.

Start with Pharmacotherapy Start with CBT

Lack of specific cognitive, or behavioral factors Need for sustained clinical improvement

Need for rapid improvement History of, or present, substance use/abuse

Time limitations Multiple comorbid medical conditions

Limited finances Hypnotic discontinuation

Shortage of trained therapists

Dietary Supplements

• Utilized by more than 50% of the US adult population• Dietary substance

– Supplements existing diet– Contains

• Vitamin• Mineral• Herb or other botanical• Amino acid• Others

– Taken orally

Bailey RL, et al. J Nutr. 2011;141(2):261-266. National Institutes of Health. Dietary Supplement Health and Education Act of 1994. Public Law 103-417. 103rd Congress. https://ods.od.nih.gov/about/dshea_wording.aspx. Accessed February 28, 2019.

Nonprescription Agents for Insomnia: Limited Evidence for Hypnotic Efficacy

Meolie AL, et al.; Clinical Practice Review Committee; American Academy of Sleep Medicine. J Clin Sleep Med. 2005;1(2):173-187.

Product Latin Name (or Generic Name) Adverse Effects

Valerian root V. officinalis L. Restless sleep, gastrointestinal upset, headache, contact allergies, mydriasis, possible carcinogen, possible hepatotoxicity

First-generation histamine-1-receptor antagonists

Diphenhydramine hydrochloride, diphenhydramine citrate, doxylamine succinate

Vomiting, depression, malaise, drowsiness, impaired mentation, extrapyramidal reactions, rhabdomyolysis, dry mouth, weakness, gastrointestinal upset, headache, impotence, urinary retention, increased intraocular pressure

Nonprescription Agents for Insomnia: Insufficient Evidence for Hypnotic Efficacy

Meolie AL, et al.; Clinical Practice Review Committee; American Academy of Sleep Medicine. J Clin Sleep Med. 2005;1(2):173-187.

Product Latin Name Adverse Effects

Hops Humulus lupulus Unknown

Chamomile Matricaria recutita Vomiting, allergic reactions

Lemon balm Melissa officinalis Unknown

St. John’s wort Hypericum perforatumFatigue, gastrointestinal upset, dizziness, anxiety, headache, photosensitivity, phototoxicity

Patrinia root Patrinia Scabiosaefolia Fisch Nausea

Niacin Niacin, niacinamide, vitamin B3 None known at recommended daily allowances

Magnesium Magnesium None known at recommended daily allowances

Vitamin B12Vitamin B12, cyanocobalamin, hydroxocobalamin, methylcobalamin

None known at recommended hydroxocobalamin, daily allowances

Dietary changes Unknown

Yoku-kan-san-ka chimpi-hange Unknown

Nonprescription Agents for Insomnia: No Evidence of Hypnotic Efficacy or Significant Safety Concerns

Meolie AL, et al.; Clinical Practice Review Committee; American Academy of Sleep Medicine. J Clin Sleep Med. 2005;1(2):173-187.

Product Latin or Scientific Name Adverse Effects

Passionflower Passiflora incarnata Dizziness, confusion, ataxia, possible prolonged QT

Californian poppy Eschscholzia californica Unknown

Wild lettuce Lactuca virosa Possible hallucinogenic

Scullcap Seizures, possible hepatotoxicity

Calcium None known at recommended daily allowances

Vitamin A None known at recommended daily allowances

5-hydroxytryptophan Unknown

Natrum muriaticum Unknown

Jamaican dogwood Piscidia piscipula Toxicity to humans

Alcohol Dependence, neurotoxicity, cardiotoxicity, myelosuppression, hepatotoxicity, respiratory depression, sedation, depression

L-tryptophan L-2-amino-3-(indole-3-yl) propionic acid Eosinophilia myalgia syndrome

Kava kava Piper methysticum Hepatotoxicity

Melatonin Meta-analysis in Primary Sleep Disorders

• 19 placebo-controlled studies, 1683 participants• Melatonin demonstrated efficacy in

– Reducing sleep latency (WMD = 7.06 minutes)– Increasing total sleep time (WMD = 8.25 minutes)

• Effects magnified with longer duration and higher doses– Improved sleep quality (standardized mean difference = 0.22)

• No significant effects of trial duration and melatonin dose

WMD = weighted mean difference.Ferracioli-Oda E, et al. PLoS One. 2013;8(5):e63773.

Melatonin Impairs Glucose Tolerance

Comparison between the effects of placebo and melatonin administrations on plasma glucose and insulin concentrations in response to an oral load of glucose (75 g) performed in the morning (09:00) and evening (21:00). TF = time fasting; T30, 60, 90, 120, and 180, time after OGTT (min); AUC120, paired t-test for AUC (melatonin and placebo) calculated with 120 min; ANOVArm, two-way ANOVA for time and treatment effects with repeated measurements. When ANOVA was significant, paired t-test was used to evaluate times in which variations were different. *Different from placebo at that time, P<.05.Rubio-Sastre P, et al. Sleep. 2014;37(10):1715-1719.

9

T120T60 T180

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T120T60 T180

Evening

Glu

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se

(mm

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)

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TF3

5

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TF3

5

8

6

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T90T30 T90T30

Time (min)

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Ins

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Ins

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T90T30 T90T30

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AUC120: P=.007ANOVArm: P=.004

AUC120: P=.0002ANOVArm: P=.001

AUC120: P=.771ANOVArm: P=.992

AUC120: P=.0002ANOVArm: P=.002

Placebo

Melatonin

*

*

*

*

*

*

*

*

*

*

*

*

Prescription Agents for Insomnia

• FDA-non-approved for insomnia– Sedating antidepressants– Antipsychotics– Anticonvulsants

• FDA-approved hypnotics– Benzodiazepine receptor agonists

• Benzodiazepines• Nonbenzodiazepines

– Melatonin receptor agonist– H1 receptor antagonist– Orexin receptor antagonist

Low Dose Sedating Antidepressants for Insomnia

• Trazodone, doxepin, mirtazapine, paroxetine• Advantages

– Sedating side effects– Low abuse risk– Large dose range

• Disadvantages– Efficacy not well established for insomnia– Side effects include daytime sedation, anticholinergic effects,

weight gain, drug-drug interactions

These agents are not FDA approved for insomnia.Kupfer DJ, et al. N Engl J Med. 1997;336(5):341-346. Sharpley AL, et al. Biol Psychiatry. 2000;47(5):468-470. Karam-Hage M, et al. Psychiatry Clin Neurosci. 2003;57(5):542-544. National Institutes of Health. Sleep. 2005;28(9):1049-1057.

Low Dose Atypical Antipsychotics for Insomnia

• Quetiapine, olanzapine• Advantages

– At appropriate doses, effective for psychotic disorders– Low abuse potential– Sedation

• Disadvantages– Not well investigated in insomnia disorder– Daytime sedation, anticholinergic effects, weight gain– Risk of extrapyramidal symptoms, possible tardive dyskinesia – Glucose and lipid abnormalities

These agents are not FDA approved for insomnia.Kupfer DJ, et al. N Engl J Med. 1997;336(5):341-346. Sharpley AL, et al. Biol Psychiatry. 2000;47(5):468-470. Karam-Hage M, et al. Psychiatry Clin Neurosci. 2003;57(5):542-544. National Institutes of Health. Sleep. 2005;28(9):1049-1057.

Which of the following brain neurotransmitters is involved in sleep generation?

A. Histamine

B. GABA

C. Serotonin

D. Norepinephrine

E. Epinephrine

Arousal and Sleep-Promoting Systems

5-HT = serotonin; Ach = acetylcholine; BF = basal forebrain; DA = dopamine; DR = dorsal raphe nucleus; GABA = gamma-aminobutyricacid; Gal = galanin; LC = locus coeruleus; LH = lateral hypothalamic; MCH = melanin-concentrating hormone; NE = norepinephrine; ORX = orexin; PPT/LDT = pedunculopontine and laterodorsal tegmental; TMN = tuberomammillary nucleus; VLPO = ventrolateral preoptic nucleus; vPAG = ventral periaqueductal gray matter.Modified from Fuller PM, et al. J Biol Rhythms. 2006;21(6):482-493. Silber MH, et al. Neurology. 2001;56(12):1616-1618.

Posterior lateral hypothalamus (orexin)

Arousal Sleep

Orexins/Hypocretins

• Hypothalamic peptides– Localized in the dorsolateral hypothalamus– Wide projections throughout the brain– Projections found in the spinal column

• Peptide neurotransmitters– Arousal – Locomotion– Metabolism– Increase blood pressure/heart rate

Peyron C, et al. J Neurosci. 1998;18(23):9996-10015. Moore RY, et al. Arch Ital Biol. 2001;139(3):195-205. Silber MH, et al. Neurology. 2001;56(12):1616-1618.

Elevated Plasma Orexin-A Levels in Insomnia Disorder

228 patients with insomnia disorder vs 282 normal sleepers.Tang S, et al. Peptides. 2017;88:55-61.

120

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-A L

eve

l (p

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Normal Sleepers Insomnia Patients

20

40

60

80

*

Benzodiazepine Receptor Agonists: Benzodiazepines

†Normal adult dose. Dosage may require individualization.MICROMEDEX. www.micromedex.com. PDR. www.PDR.net.

MedicationDosage Range†

(mg) Onset of Action

Half-life(h)

Short-term Limitation?

Estazolam 0.5–2 Rapid 10–24 Yes

Flurazepam 15–30 Rapid 47–100 Yes

Quazepam 7.5–15 Rapid 39–100 Yes

Temazepam 7.5–15Slow–

Intermediate9.5–12.4 Yes

Triazolam 0.25–0.50 Rapid 1.5–5.5 Yes

A 60-year-old man complains of insomnia; he falls asleep rapidly after going to bed, but wakes up repeatedly starting at 1 AM, feeling fatigued the next day.

What is the least appropriate medication?

A. Zolpidem ERB. RamelteonC. EszopicloneD. Doxepin low doseE. Suvorexant

Selective Benzodiazepine Receptor Agonists

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

Zaleplon Zolpidem Zolpidem ER Eszopiclone

Dose (mg) [elderly] 5, 10, 20 [5] 5, 10 [5] 6.25, 12.5 [6.25] 1, 2, 3 [1]

Tmax (hours) 1 1.6 1.5 1

Half-life (hours) [elderly] 1 2.5 [2.9] 2.8 [2.9] 6 [9]

Sleep Latency ↓ ↓ ↓ ↓

Wake after Sleep Onset -- -- ↓ ↓

Total Sleep Time↑

(20 mg)↑ ↑ ↑

Schedule IV IV IV IV

Newer Hypnotics

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

Ramelteon Doxepin Suvorexant

MechanismMelatonin receptor

agonistH1 receptor antagonist

Dual orexin receptor antagonist

Dose (mg) [elderly] 8 3, 6 [3] 10–20

Tmax (hours) 0.75 3.5 2

Half-life (hours) [elderly]

1–2.6 15.3 12

Sleep Latency ↓ -- ↓

Wake after Sleep Onset -- ↓ ↓

Total Sleep Time -- -- ↑

Schedule None None IV

Zolpidem Variants

MOTN = middle-of-the-night; SL = sublingual.US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

Zolpidem Zolpidem SL Zolpidem SL Zolpidem Oral Spray

Dose (mg) [elderly] 5,10 [5] 5,10 [5]

Men: 3.5; Women: 1.75 [1.75]

MOTN, 4 hours remaining until AM awakening

5,10 [5]

Tmax (hours) 1.6 1.4 1.3 0.9

Half-life (hours) [elderly] 2.5 [2.9] 2.9 2.5 2.7

Adverse Effects of Hypnotics

• Benzodiazepine receptor agonists– Daytime sedation, psychomotor and

cognitive impairment (depending on dose and half-life)

– Rebound insomnia – Respiratory depression in vulnerable

populations – DEA Schedule IV

• Melatonin receptor agonist– Headache, somnolence, fatigue,

dizziness– Not recommended for use with

fluvoxamine due to CYP 1A2 interaction

• H1 receptor antagonist– Somnolence/sedation– Nausea– Upper respiratory tract infection

• Orexin receptor antagonist– Somnolence– Risk of impaired alertness and motor

coordination, including impaired driving; increases with dose

– Contraindicated in narcolepsy– DEA Schedule IV

Mitler MM. Sleep. 2000;23 Suppl 1:S39-S47. Holbrook AM, et al. CMAJ. 2000;162(2):225-233. Charney DS, et al. In: Hardman JG, et al (Eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Tenth Edition. McGraw Hill; 2001:399-427. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. MICROMEDEX. www.micromedex.com.

Driving Safety: MOTN Low-Dose Zolpidem SL

SDLP = standard deviation of lateral position; SL = sublingual; ZOP = zopiclone; ZST = zolpidem sublingual tablet.Vermeeren A, et al. Sleep. 2014;37(3):489-496.

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The risk of parasomnias during hypnotic use is enhanced by:

A. Co-administration with sedating agents

B. MDD

C. Younger age

D. Female gender

E. Lower socioeconomic status

Zolpidem-Induced Parasomnias

• Spontaneous reports• Sleep-driving; preparing and eating food, making phone calls, or having sex • Amnesia for events• Risk factors

– Co-use of alcohol or sedatives– Use at doses exceeding the maximum recommended dose– Sleep disorder: OSA or PLMS– H/O parasomnia– Ingestion at unusual bedtime– Ingestion while agitated or not typically asleep– Ingestion when sleep deprived– Poor management of pill bottles– Living alone

PLMS = periodic limb movements of sleep; OSA = obstructive sleep apnea. Poceta JS. J Clin Sleep Med. 2011;7(6):632-638.

Selected Considerations in Choosing a Hypnotic Agent

• Initiation or maintenance insomnia– Initiation: Zaleplon, zolpidem, ramelteon– Maintenance: Doxepin low dose, zolpidem SL MOTN– Initiation and maintenance: Zolpidem ER, eszopiclone, suvorexant

• Respiratory compromise; safety in mild to moderate OSA/COPD– Ramelteon, suvorexant

• Abuse potential– Lowest: Ramelteon, doxepin

• Prior failure of selected medication• Patient preference

COPD = chronic obstructive pulmonary disease.PDR. www.PDR.net. Sun H, et al. J Clin Sleep Med. 2016;12(1):9-17. Kryger M, et al. Sleep Breath. 2007;11(3):159-164.

Insomnia Complaints in MDD

• 80% inpatients • 40% outpatients• Reduced quantity

– Initial– Middle– Early morning awakening

• Reduced quality• Unrefreshing sleep

Reynolds CF 3rd, et al. Sleep. 1987;10(3):199-215.

RCTs of Hypnotic Agents in Conjunction with SSRI in MDD

• Zolpidem 10 mg vs PBO for persistent insomnia following SSRI (fluoxetine, sertraline, paroxetine) Rx for MDD or dysthymia– Improvement in subjective sleep measures

• Zolpidem ER 12.5 mg plus escitalopram vs PBO plus escitalopram in MDD patients with insomnia– Improvement in subjective sleep measures– Improvement in next day functioning

• Eszopiclone 3 mg plus fluoxetine vs PBO plus fluoxetine in MDD patients with insomnia – Improved subjective sleep measures– Improved quality of life – Higher overall MDD remission rates

• Suvorexant 10 to 20 mg vs PBO for persistent insomnia following stable antidepressant management for MDD– Study in progress at 3 sites

Hypnotics are not FDA indicated for treatment of MDD. PBO = placebo; SSRI = selective serotonin reuptake inhibitor. Asnis GM, et al. J Clin Psychiatry. 1999;60(10):668-676. Fava M, et al. Biol Psychiatry. 2006;59(11):1052-1060. Fava M, et al. J Clin Psychiatry. 2011;72(7):914-928. McCall WV, et al. J Clin Sleep Med. 2010;6(4):322-329. ClinicalTrials.gov Identifier: NCT02669030.

Hypnotics Under Development

• Dual and single orexin receptor antagonists– Lemborexant– TCS OX2 29– Seltorexant

• Benzodiazepine receptor agonists– Controlled release zaleplon– Inhaled zaleplon– Lorediplon– EVT 201

• Melatonin receptor agonists– Controlled release melatonin for

elderly (Circadin®)– Piromelatine– Others

• Beta-blockers• Histamine H1 antagonists• 5-HT2A receptor antagonists • Adenosine receptor agonists• Angiotensin II receptor 1 antagonist• Cannabinoid agonist

Lemborexant• Dual orexin receptor antagonist; is thought to regulate sleep and wake by dampening

wakefulness without hindering the ability to awaken to external stimuli• Controlled study in insomnia disorder demonstrated improvement in sleep latency and

continuity• Phase 2 study under way for irregular sleep-wake rhythm disorder and mild to moderate

Alzheimer’s dementia• New drug application (NDA) submitted to FDA for insomnia disorder January 15, 2019

– SUNRISE 1 and SUNRISE 2; N=~2000– SUNRISE 1: 1-month, double-blind, placebo-controlled study; Phase 3 head-to-head

comparison vs zolpidem ER; objectively assessed sleep parameters (time to sleep onset, sleep efficiency, and wake after sleep onset)

– SUNRISE 2: 12-month study; subjectively assessed for ability to fall asleep and stay asleep based on patient self reports (sleep diaries)

• Adverse effects: Somnolence, headache, sleep paralysis, rapid eye movements abnormal sleep, nightmare, abnormal dreams, dizziness, back pain, hypnagogic hallucinations, myalgia, feeling drunk

Murphy P, et al. J Clin Sleep Med. 2017;13(11):1289-1299. Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1). ClinicalTrials.gov Identifier: NCT02783729. Long-term Study of Lemborexant in Insomnia Disorder (SUNRISE 2). ClinicalTrials.gov Identifier: NCT02952820.

Lemborexant Morning Driving Performance and MOTN Body Sway

*A unit of body sway is defined as 1/3 degree angle of arc movement of the ataxiameter. Dashed horizontal line indicates threshold for clinically meaningful change from baseline.Vermeeren A, et al. Sleep. 2018 Dec 31;[Epub ahead of print]. Murphy P, et al. Auditory awakening threshold to evaluate ability to awaken after administration of lemborexant versus zolpidem. Sleep. 2018;41(Suppl 1):A156- A157.

30

LS

Me

an (

95%

CI)

Ch

an

ge

fro

m B

ase

line

in B

od

y S

way

(u

nit

s*)

0

-10

10

Middle of the Night

20Placebo (N=56)

Zolpidem 6.25 mg (N=56)

Lemborexant 5 mg (N=56)

Lemborexant 10 mg (N=56)

10

Ind

ivid

ua

l SD

LP

Dif

fere

nc

efr

om

Pla

ceb

o V

alu

e (c

m)

-8

-10

-2

4

6

-6

0

8

-4

2

LEM 2.5(N=32)

ZOP(N=48)

LEM 10(N=32)

LEM 5(N=32)

Day 2

LEM 2.5(N=32)

ZOP(N=48)

LEM 10(N=32)

LEM 5(N=32)

Day 9

Lemborexant 2.5 mgLemborexant 5 mgLemborexant 10 mg

Means with 95% CIZopiclone 7.5 mg

-2.4

2.4

The Future in Insomnia Treatments

• Refining pharmacotherapy– Higher efficacy, remission (cure?)– Fewer side effects– Novel mechanisms – Selection of hypnotic based on receptor profile or comorbid

conditions• Development of hypnotic devices

– Mobile electronics to stratify and treat insomnia– Thermal devices

• Online CBT• Improving health outcomes through insomnia treatment

Conclusions

• Insomnia is highly prevalent in psychiatric patients• It is associated with psychological and physical impairments and

enhances the risk of psychiatric conditions• Management begins with a systematic evaluation followed by

treatment of comorbidities• Whenever possible, treat the comorbid disorder• Insomnia can be directly managed by CBT and pharmacologic

agents